Project Summary/Abstract Drawing the fundamental blueprint of tumorigenesis and cancer metabolism is an important and urgent issue for providing proper targets of cancer therapy. Drosophila has long served as a genetic model for many developmental processes, but its usefulness as a cancer research model has only recently been appreciated. The signaling pathways that control glycolysis, tissue growth, cell survival, cell migration, and mechanisms for enhancing oxygen supply to tumors in Drosophila show remarkable conservation with mammalian systems. This study utilizes powerful genetic tools and reagents available for the Drosophila model system to understand how signaling pathways and metabolic enzymes affect tumor behavior. In particular, we will determine the cause and function of aberrant and seemingly non-functional Notch accumulation during tumor formation as well as analyze oxygen supply and metastasis within the malignant tumor to assess how glycolysis, mitochondrial activity, and TCA cycle are involved and influenced. This proposal consists of three major aims. Aim 1 describes experiments aimed at discovering the molecular mechanism of aberrant Notch accumulation and proposed non-canonical function in glycolytic tumors. In Aim 2 we propose to characterize the regulatory factors on metabolic reprogramming during angiogenesis and metastasis. Finally, in Aim 3, we will identify and characterize the non- dual function of a glycolytic enzyme, which has a great potential to be a target of human cancer therapy. The research we propose will lead to critical insights into how the signaling pathways and glycolytic enzymes regulate cancer metabolism and influence tumor progression. The PI will be involved in mentoring and supervision of the work that will involve the training of 2 postdoctoral fellows and 1 graduate student dedicated to this work. Additionally, the laboratory traditionally trains a large number of undergraduates in research. The typical undergraduate spends 2-3 years in the laboratory; postdocs, 5 years and graduate students 5-6 years. The main scientific disciplines our research encompasses developmental biology and genetics. All graduate and postdoctoral researchers involved are highly knowledgeable in these two fields, and the more experienced members of the lab typically pass along this familiarity to newer members.